AGING AND DOPAMINE GRAFTS IN PARKINSONIAN MONKEYS

帕金森病猴的衰老和多巴胺移植

• 批准号: 6372380
• 负责人: Timothy J. Collier
• 金额: $ 72.9万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372380
• 关键词: Macaca mulatta; Parkinson's disease; age difference; angiogenesis; apoptosis; basal ganglia; denervation; dopamine; dopamine receptor; embryo /fetus tissue transplantation; experimental brain lesion; homologous transplantation; juvenile animal; mature animal; mesencephalon; methylphenyltetrahydropyridine; necrosis; neurons; neurotrophic factors; nonhuman therapy evaluation; oxidative stress; prognosis; receptor binding

DESCRIPTION: (Verbatim from the Applicant's Abstract) Transplantation of embryonic dopamine (DA) neurons as an experimental therapy for Parkinson's disease (PD) is currently under evaluation. The non-human primate treated with the neurotoxin MPTP has served as an important animal model for the disease and the grafting paradigm, and has had significant predictive value for results of early clinical trials. Despite some encouraging clinical findings, relative survival of grafted DA neurons is low and improvement of behavioral symptoms is incomplete. Part of the disparity between results in animals and PD patients may relate to failure of animal studies to model certain characteristics of potential recipients of graft therapy that impact significantly on the environment of grafted cells. One characteristic of this patient population that can be examined in animals is the influence of chronological age of the transplant recipient. The interactions between age-related changes inherent to this system in graft recipients, the response of the aging system to accelerated loss of nigral DA neurons, and the impact these changes have on the environment for grafted tissue only recently have received attention. We have found that the viability and function of grafted DA neurons is profoundly diminished in DA-depleted aged rats. In addition, these aged animals exhibit important deficits in compensatory responses to DA depletion including decreased striatal neurotrophic activity. Recent clinical results also suggest diminished graft efficacy in elderly patients. Advancing chronological age of the transplant recipient may represent a previously under-appreciated risk of diminished graft viability and function that may mandate study of novel grafting strategies 1 to achieve good therapeutic results. It is the goal of this proposal to evaluate the influence of chronological age of the host on graft viability and function in MM?-treated non-human primates. Tissue from single donors will be divided for implantation into pairs of young adult and aged hemiparkinsonian monkeys, with behavioral, mophological, and biochemical techniques employed to study rates of apoptosis in grafts, survivai, neurite outgrowth and release of DA from grafted cells, and receptor, metabolic and -trophic responses in the host. Additional analyses will examine aging-related changes in microvasculature and oxidative stress in the graft environment. These studies will provide valuable information on the response of the aged brain to accelerated DA neuron loss, the interaction between aging in the host and graft viability, indicate mechanisms of intervention with graft survival and function in the aged brain, and will aid in matching patients with the optimal therapeutic approach.

描述：（逐字摘自申请人摘要）移植 胚胎多巴胺（DA）神经元作为帕金森病的实验疗法 疾病（PD）目前正在评估中。接受治疗的非人类灵长类动物 神经毒素 MPTP 已成为该疾病的重要动物模型 嫁接范式，并对结果具有显着的预测价值 早期临床试验。尽管有一些令人鼓舞的临床发现，相对 移植的 DA 神经元存活率低，行为症状改善缓慢 不完整。动物和 PD 患者结果之间的部分差异 可能与动物研究未能模拟某些特征有关 移植治疗的潜在接受者对移植治疗有重大影响 移植细胞的环境。该患者群体的一个特征 可以在动物身上检查的是实际年龄的影响 移植受者。与年龄相关的变化之间的相互作用 移植受者的这个系统，老化系统的反应 黑质 DA 神经元的加速损失，以及这些变化对 移植组织的环境最近才受到关注。我们有 发现移植的 DA 神经元的活力和功能 DA 耗尽的老年大鼠中减少。此外，这些年老的动物表现出 对 DA 消耗的补偿反应存在严重缺陷，包括 纹状体神经营养活性降低。最近的临床结果还表明 老年患者的移植物疗效降低。实际年龄提前 移植受者可能代表了以前被低估的风险 移植物活力和功能降低，可能需要研究新的 嫁接策略 1.取得良好的治疗效果。它的目标是 该提案旨在评估主持人的实际年龄对 MM?处理的非人类灵长类动物的移植物活力和功能。组织来自 单个捐赠者将被分成成对的年轻成人和 老年偏帕金森病猴，具有行为、形态和生化特征 用于研究移植物凋亡率、存活率、神经突的技术 移植细胞以及受体、代谢和 DA 的生长和释放 -宿主的营养反应。额外的分析将检查与衰老相关的 移植物环境中微血管和氧化应激的变化。 这些研究将为老年人的反应提供有价值的信息 大脑加速DA神经元损失、宿主衰老之间的相互作用 和移植物活力，表明移植物存活的干预机制 和老年大脑的功能，并将有助于将患者与老年大脑相匹配 最佳治疗方法。